DNA Mismatch Repair Mechanisms in Eukaryotic and Prokaryotic Systems

DNA mismatch repair (MMR) is a fundamental pathway that maintains genomic integrity by recognising and correcting errors introduced during DNA replication and recombination. In prokaryotes, the canonical system relies on MutS to detect base–base mismatches and insertion–deletion loops, and on MutL to coordinate excision and resynthesis of the erroneous strand. Strand discrimination is often guided by methylation patterns. In eukaryotes, conserved homologues—MSH2–MSH6 or MSH2–MSH3 complexes for mismatch recognition, and MLH1–PMS2 for downstream processing—operate in concert with accessory factors such as exonucleases and proliferating cell nuclear antigen (PCNA). Beyond replication, MMR intersects with recombination pathways, heteroduplex rejection and the response to DNA damage. Variations in MMR efficiency underlie hypermutation phenotypes in cancer, microbial adaptation to environmental pressures and the evolution of pathogens. Comparative studies across bacterial, archaeal and eukaryotic models have revealed both shared biochemical core activities and lineage-specific adaptations, including non-canonical endonucleases in archaea and strand-bias influences from DNA end structures. The global significance of MMR extends to cancer therapy, antimicrobial resistance and the engineering of genome-editing tools.

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Technical terms

Mismatch repair (MMR): A pathway that identifies and corrects mispaired bases and small insertion–deletion loops in DNA.

MutS/MutL homologues: Protein complexes that detect mismatches (MutS) and coordinate the excision and resynthesis steps (MutL).

Heteroduplex rejection: A process whereby mismatched DNA intermediates in recombination are unwound rather than repaired, preventing homeologous recombination.

Single-strand annealing (SSA): A DNA double-strand break repair mechanism that aligns homologous repeats and removes intervening sequences, often producing mismatches at annealed regions.

3′ flap: A single-stranded overhang at the 3′ end created during end resection, which can influence repair pathway choices and strand discrimination.

References

1. Nonhomologous tails direct heteroduplex rejection and mismatch correction during single-strand annealing in Saccharomyces cerevisiae. PLOS Genetics (2024).
2. Strand asymmetry influences mismatch resolution during single-strand annealing. Genome Biology (2022).
3. Mutation rate and spectrum in obligately outcrossing Caenorhabditis elegans mutation accumulation lines subjected to RNAi-induced knockdown of the mismatch repair gene msh-2. G3: Genes, Genomes, Genetics (2021).
4. Functional Analysis of the NucS/EndoMS of the Hyperthermophilic Archaeon Sulfolobus islandicus REY15A. Frontiers in Microbiology (2020).